title: Deregulation of Fragile X-related protein 1 by the lipodystrophic lamin A p.R482W mutation elicits a myogenic gene expression program in preadipocytes.
abstract: The nuclear lamina is implicated in the regulation of various nuclear functions. Several laminopathy-causing mutations in the LMNA gene, notably the p.R482W substitution linked to familial partial lipodystrophy type 2 (FPLD2), are clustered in the immunoglobulin fold of lamin A. We report a functional association between lamin A and fragile X-related protein 1 (FXR1P), a protein of the fragile X-related family involved in fragile X syndrome. Searching for proteins differentially interacting with the immunoglobulin fold of wild-type and R482W mutant lamin A, we identify FXR1P as a novel component of the lamin A protein network. The p.R482W mutation abrogates interaction of FXR1P with lamin A. Fibroblasts from FPLD2 patients display elevated levels of FXR1P and delocalized FXR1P. In human adipocyte progenitors, deregulation of lamin A expression leads to FXR1P up-regulation, impairment of adipogenic differentiation and induction of myogenin expression. FXR1P overexpression also stimulates a myogenic gene expression program in these cells. Our results demonstrate a cross-talk between proteins hitherto implicated in two distinct mesodermal pathologies. We propose a model where the FPLD2 lamin A p.R482W mutation elicits, through up-regulation of FXR1P, a remodeling of an adipogenic differentiation program into a myogenic program.
authors.affiliation: Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences and Norwegian Center for Stem Cell Research, Faculty of Medicine, University of Oslo, PO Box 1112, Blindern, Oslo 0317, Norway.
authors.forename: Anja R
authors.initials: AR
authors.lastname: Oldenburg
authors.forename: Erwan
authors.initials: E
authors.lastname: Delbarre
authors.forename: Bernd
authors.initials: B
authors.lastname: Thiede
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
authors.forename: Philippe
authors.initials: P
authors.lastname: Collas
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002454:Cell Differentiation / Q000235:genetics; D003062:Codon; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism; D052496:Lipodystrophy, Familial Partial / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000235:genetics*; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D003062:Codon; C096916:FXR1 protein, human; D034904:Lamin Type A; D010455:Peptides; D016601:RNA-Binding Proteins